Project B is the source of the pool of narcoleptic subjects, diagnosed in a standardized manner. Formerly, the Stanford Center for Narcolepsy used as inclusion criteria the unequivocal presence of cataplexy and excessive daytime sleepiness verified by MSLT (mean sleep latency equal to or less than 8 minutes with equal to or more than 2 sleep onset REM periods or SOREMPs). All clinical cases were then blindly reviewed by a member of our group prior to inclusion and correlation with HLA typing results. We have shown that cataplexy, rather than polygraphic measures, can be the principal entrance criteria for our studies. The unequivocal presence of cataplexy is the best predictor for the syndrome. This will enable us to undertake worldwide data gathering, since it is often difficult to obtain MSLT data; some sleep centers in the U.S. and most centers in Europe and Asia, often use polysomnographic measures other than the MSLT. Due to our wish to include patients referred from other centers in a more flexible way after careful review of their clinical histories, we decided to include all patients with cataplexy, independent of polygraphic test results. The clarity of calaplexy will be assessed from clinical histories provided by the referring physician and on responses to our recently developed sleep inventory. Patients will then be assigned a rating category, depending on responses to cataplexy-related items and the polysomnographic or MSLT data. The sleep inventory will soon be validated in a large number of patients and controls. Using the revised entrance criteria, we have completed collection of data and samples from 189 patients of various ethnic groups with sporadic cases of narcolepsy-cataplexy (135 with clear cut cataplexy). Our projected quotas of sporadic patients with clear cut cataplexy for the next 5 years are 100 Blacks, 100 Caucasians, 50 Asians, 10 Latinos, and 20 subjects of mixed ethnicity; these quotas are the minimum necessary for our human genetic studies. Samples from a total of 130 HLA-typed Black controls have also been collected, and HLA-typed Caucasian controls and homozygous cell lines are in unlimited supply through the Stanford University Blood Bank. We plan to collect samples from an equal number of ethnically matched controls for each ethnic group studied. We will also continue to collect samples from rare non- DQB1-0602 narcoleptic patients with sporadic cases of narcolepsy through international liaisons. We have gathered samples from 27 such patients (16 with clear cut cataplexy) and plan to bring this group 10 a total of 30 patients over the next 5 years. Collection of data and samples has been completed for 20 multiplex families with more than one narcoleptic-cataplectic family member. Four families are non-DR2 and show no linkage of susceptibility to disease with the DR locus. In the other 16 families, all affected family members arc DR2-positive. Data collection for 10 additional families (8 DR2- positive, 2 DR2 negative) has been initiated. Application of our cataplexy rating codes to the multiplex families, whose members often present partial symptoms of the narcolepsy syndrome, has assisted in the organization of the familial data. In the next funding period, we anticipate increasing our completed multiplex pedigrees to 40 families. This Project also includes the bank of samples for biological analysis. Blood samples are processed by isolating lymphocytes, which are used for HLA typing and DNA extraction. Information pertaining to sample origin is maintained in computerized databases. Together with the clinical data, the genetic data will contribute to our goal of unravelling the etiology of human narcolepsy.